AIF-regulated oxidative phosphorylation supports lung cancer development

• Published in: Cell research Vol. 29; no. 7; pp. 579 - 591
• Main Authors: Rao, Shuan, Mondragón, Laura, Pranjic, Blanka, Hanada, Toshikatsu, Stoll, Gautier, Köcher, Thomas, Zhang, Peng, Jais, Alexander, Lercher, Alexander, Bergthaler, Andreas, Schramek, Daniel, Haigh, Katharina, Sica, Valentina, Leduc, Marion, Modjtahedi, Nazanine, Pai, Tsung-Pin, Onji, Masahiro, Uribesalgo, Iris, Hanada, Reiko, Kozieradzki, Ivona, Koglgruber, Rubina, Cronin, Shane J., She, Zhigang, Quehenberger, Franz, Popper, Helmut, Kenner, Lukas, Haigh, Jody J., Kepp, Oliver, Rak, Malgorzata, Cai, Kaican, Kroemer, Guido, Penninger, Josef M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2019; Nature Publishing Group
• Subjects: 13/106; 13/89; 14/28; 14/63; 631/67/1612/1350; 631/80/304; 64/110; 82; 82/51; 96; Animals; Apoptosis; Apoptosis Inducing Factor - physiology; Apoptosis-inducing factor; Bioenergetics; Biomedical and Life Sciences; Carcinogenesis - metabolism; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Line, Tumor; Clonal deletion; Datasets as Topic; Disease Progression; Electron transport; Glycolysis; Humans; Life Sciences; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical prognosis; Medicin och hälsovetenskap; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; Non-small cell lung carcinoma; Oxidative Phosphorylation; Phosphorylation; Pneumocytes; Survival; Tumor cells; Tumors
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/s41422-019-0181-4

Cancer is a major and still increasing cause of death in humans. Most cancer cells have a fundamentally different metabolic profile from that of normal tissue. This shift away from mitochondrial ATP synthesis via oxidative phosphorylation towards a high rate of glycolysis, termed Warburg effect, has long been recognized as a paradigmatic hallmark of cancer, supporting the increased biosynthetic demands of tumor cells. Here we show that deletion of apoptosis-inducing factor (AIF) in a Kras G12D -driven mouse lung cancer model resulted in a marked survival advantage, with delayed tumor onset and decreased malignant progression. Mechanistically, Aif deletion leads to oxidative phosphorylation (OXPHOS) deficiency and a switch in cellular metabolism towards glycolysis in non-transformed pneumocytes and at early stages of tumor development. Paradoxically, although Aif -deficient cells exhibited a metabolic Warburg profile, this bioenergetic change resulted in a growth disadvantage of Kras G12D -driven as well as Kras wild-type lung cancer cells. Cell-autonomous re-expression of both wild-type and mutant AIF (displaying an intact mitochondrial, but abrogated apoptotic function) in Aif -knockout Kras G12D mice restored OXPHOS and reduced animal survival to the same level as AIF wild-type mice. In patients with non-small cell lung cancer, high AIF expression was associated with poor prognosis. These data show that AIF-regulated mitochondrial respiration and OXPHOS drive the progression of lung cancer.